Clinical and experimental observations tend to link the predilection of ZZ homozygotes for chronic obstructive pulmonary disease (COPD) to their low serum alpha 1-anti-trypsin (AAT) in relation to protease normally released in lung by sequestered leukocytes and by alveolar macrophages. Yet some homozygotes, sometimes members of the same family, avoid lung disease entirely or until late in life, for reasons yet to be explained. This suggests that AAT deficiency may be only one of many determinants, including genetic, environmental, or local protective mechanisms of lung. The interplay and cumulative effects of such factors could be important determinants of whether COPD occurs and how it progresses. A major objective is to investigate whether variation in the level of polymorphonuclear (PMN) leukocyte lysosomal protease activity among different persons, perhaps genetically controlled, is in conjunction with variation in AAT, a determining factor. If this were so, high protease activity in relation to AAT would favor development of COPD and low protease activity would be protective against COPD. We also have the objective of investigating whether cigarette smoking and PMN leukocyte lysosomal protease have additive or synergistic effects in COPD. In addition, we will study the effect of cigarette smoking and alveolar macrophage lysosomal protease activity on protease-antiprotease balance in bronchial secretions. Knowledge of the influence of these several factors on the protease-antiprotease balance could lead to new insight into the pathogenesis of COPD and, ultimately, to new methods for prevention and treatment.